Treatment and outcomes in children with multidrug-resistant tuberculosis : a systematic review and individual patient data meta-analysis.
Date
2018-07-11
Journal Title
Journal ISSN
Volume Title
Publisher
Public Library of Science
Abstract
Background:
An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium
tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the
optimal treatment for these children.
Methods and findings: To inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB
treatment guidelines, we performed a systematic review and individual patient data (IPD)
meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify
eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO,
and BioMedCentral databases through 1 October 2014. To identify unpublished
data, we reviewed conference abstracts, contacted experts in the field, and requested data
through other routes, including at national and international conferences and through organizations
working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum
of three children (aged <15 years) who were treated for bacteriologically confirmed or
clinically diagnosed MDR-TB, and if treatment outcomes were reported. The search yielded
2,772 reports; after review, 33 studies were eligible for inclusion, with IPD provided for 28 of
these. All data were from published or unpublished observational cohorts. We analyzed
demographic, clinical, and treatment factors as predictors of treatment outcome. In order to
obtain adjusted estimates, we used a random-effects multivariable logistic regression (random
intercept and random slope, unless specified otherwise) adjusted for the following
covariates: age, sex, HIV infection, malnutrition, severe extrapulmonary disease, or the
presence of severe disease on chest radiograph. We analyzed data from 975 children from
18 countries; 731 (75%) had bacteriologically confirmed and 244 (25%) had clinically diagnosed
MDR-TB. The median age was 7.1 years. Of 910 (93%) children with documented
HIV status, 359 (39%) were infected with HIV. When compared to clinically diagnosed
patients, children with confirmed MDR-TB were more likely to be older, to be infected with HIV, to be malnourished, and to have severe tuberculosis (TB) on chest radiograph (p <
0.001 for all characteristics). Overall, 764 of 975 (78%) had a successful treatment outcome
at the conclusion of therapy: 548/731 (75%) of confirmed and 216/244 (89%) of clinically
diagnosed children (absolute difference 14%, 95% confidence interval [CI] 8%±19%, p <
0.001). Treatment was successful in only 56% of children with bacteriologically confirmed
TB who were infected with HIV who did not receive any antiretroviral treatment (ART) during
MDR-TB therapy, compared to 82% in children infected with HIV who received ART during
MDR-TB therapy (absolute difference 26%, 95% CI 5%±48%, p = 0.006). In children with
confirmed MDR-TB, the use of second-line injectable agents and high-dose isoniazid (15±
20 mg/kg/day) were associated with treatment success (adjusted odds ratio [aOR] 2.9, 95%
CI 1.0±8.3, p = 0.041 and aOR 5.9, 95% CI 1.7±20.5, p = 0.007, respectively). These findings
for high-dose isoniazid may have been affected by site effect, as the majority of patients
came from Cape Town. Limitations of this study include the difficulty of estimating the treatment
effects of individual drugs within multidrug regimens, only observational cohort studies
were available for inclusion, and treatment decisions were based on the clinician's perception
of illness, with resulting potential for bias.
Conclusions: This study suggests that children respond favorably to MDR-TB treatment. The low success
rate in children infected with HIV who did not receive ART during their MDR-TB treatment
highlights the need for ART in these children. Our findings of individual drug effects on treatment
outcome should be further evaluated.
Description
CITATION: Harausz, E. P., et al. 2018. Treatment and outcomes in children with multidrug-resistant tuberculosis : a systematic review and individual patient data meta-analysis. PLoS Medicine, 15(7):e1002591, doi:10.1371/journal.pmed.1002591.
The original publication is available at https://journals.plos.org/plosmedicine
The original publication is available at https://journals.plos.org/plosmedicine
Keywords
Tuberculosis, Multidrug-resistant tuberculosis, Medicine -- Research -- Evaluation, Isoniazid, Rifampin, Tuberculosis in children -- Treatment
Citation
Harausz, E. P., et al. 2018. Treatment and outcomes in children with multidrug-resistant tuberculosis : a systematic review and individual patient data meta-analysis. PLoS Medicine, 15(7):e1002591, doi:10.1371/journal.pmed.1002591